scholarly journals trans-Cinnamaldehyde Inhibits Microglial Activation and Improves Neuronal Survival against Neuroinflammation in BV2 Microglial Cells with Lipopolysaccharide Stimulation

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Yan Fu ◽  
Pin Yang ◽  
Yang Zhao ◽  
Liqing Zhang ◽  
Zhangang Zhang ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Microglial Activation ◽  
Neuronal Damage ◽  
Neuronal Survival ◽  
Microglial Cells ◽  
Neuroprotective Effects ◽  
Bv2 Cells ◽  
Parkinson’S Diseases ◽  
Cox 2 ◽  
Bv2 Microglial Cells

Background.Microglial activation contributes to neuroinflammation and neuronal damage in neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. It has been suggested that neurodegenerative disorders may be improved if neuroinflammation can be controlled.trans-cinnamaldehyde (TCA) isolated from the stem bark ofCinnamomum cassiapossesses potent anti-inflammatory capability; we thus tested whether TCA presents neuroprotective effects on improving neuronal survival by inhibiting neuroinflammatory responses in BV2 microglial cells.Results.To determine the molecular mechanism behind TCA-mediated neuroprotective effects, we assessed the effects of TCA on lipopolysaccharide- (LPS-) induced proinflammatory responses in BV2 microglial cells. While LPS potently induced the production and expression upregulation of proinflammatory mediators, including NO, iNOS, COX-2, IL-1β, and TNF-α, TCA pretreatment significantly inhibited LPS-induced production of NO and expression of iNOS, COX-2, and IL-1βand recovered the morphological changes in BV2 cells. TCA markedly attenuated microglial activation and neuroinflammation by blocking nuclear factor kappa B (NF-κB) signaling pathway. With the aid of microglia and neuron coculture system, we showed that TCA greatly reduced LPS-elicited neuronal death and exerted neuroprotective effects.Conclusions.Our results suggest that TCA, a natural product, has the potential of being used as a therapeutic agent against neuroinflammation for ameliorating neurodegenerative disorders.

scholarly journals Suppression of LPS-Induced Inflammation and Cell Migration by Azelastine through Inhibition of JNK/NF-κB Pathway in BV2 Microglial Cells

2021 ◽  
Vol 22 (16) ◽  
pp. 9061
Author(s):  
Phuong Linh Nguyen ◽  
Bich Phuong Bui ◽  
Men Thi Hoai Duong ◽  
Kyeong Lee ◽  
Hee-Chul Ahn ◽  
...  
Keyword(s):  
Cell Migration ◽  
Inflammatory Mediators ◽  
Nuclear Translocation ◽  
Drug Repurposing ◽  
Microglial Cells ◽  
Potential Candidate ◽  
Jnk Pathway ◽  
Bv2 Cells ◽  
Parkinson’S Diseases ◽  
Bv2 Microglial Cells

The c-Jun N-terminal kinases (JNKs) are implicated in many neuropathological conditions, including neurodegenerative diseases. To explore potential JNK3 inhibitors from the U.S. Food and Drug Administration-approved drug library, we performed structure-based virtual screening and identified azelastine (Aze) as one of the candidates. NMR spectroscopy indicated its direct binding to the ATP-binding site of JNK3, validating our observations. Although the antihistamine effect of Aze is well documented, the involvement of the JNK pathway in its action remains to be elucidated. This study investigated the effects of Aze on lipopolysaccharide (LPS)-induced JNK phosphorylation, pro-inflammatory mediators, and cell migration in BV2 microglial cells. Aze was found to inhibit the LPS-induced phosphorylation of JNK and c-Jun. It also inhibited the LPS-induced production of pro-inflammatory mediators, including interleukin-6, tumor necrosis factor-α, and nitric oxide. Wound healing and transwell migration assays indicated that Aze attenuated LPS-induced BV2 cell migration. Furthermore, Aze inhibited LPS-induced IκB phosphorylation, thereby suppressing nuclear translocation of NF-κB. Collectively, our data demonstrate that Aze exerts anti-inflammatory and anti-migratory effects through inhibition of the JNK/NF-κB pathway in BV2 cells. Based on our findings, Aze may be a potential candidate for drug repurposing to mitigate neuroinflammation in various neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases.

scholarly journals Qingkailing Suppresses the Activation of BV2 Microglial Cells by Inhibiting Hypoxia/Reoxygenation-Induced Inflammatory Responses

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Lulu Mana ◽  
Shan Wang ◽  
Haiyan Zhu ◽  
Yanwei Xing ◽  
Lixia Lou ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Microglial Cells ◽  
Inflammatory Factor ◽  
Bv2 Cells ◽  
Cox 2 ◽  
Bv2 Microglial Cells ◽  
Hypoxia Reoxygenation

Qingkailing (QKL) is a well-known composite extract used in traditional Chinese medicine. This extract has been extensively administered to treat the acute phase of cerebrovascular disease. Our previous experiments confirmed that QKL exerts an inhibitory effect on cerebral ischemia-induced inflammatory responses. However, whether QKL suppresses the activation of microglia, the primary resident immune cells in the brain, has yet to be determined. In this study, BV2 microglial cells were used to validate the protective effects of QKL treatment following ischemia-reperfusion injury simulated via hypoxia/reoxygenationin vitro. Under these conditions, high expression levels of ROS, COX-2, iNOS, and p-p38 protein were detected. Following ischemia/reperfusion injury, QKL significantly increased the activity of BV2 cells to approximately the basal level by modulating microglial activation via inhibition of inflammatory factors, including TNF-α, COX-2, iNOS, and p-p38. However, QKL treatment also displayed dose-dependent differences in its inhibitory effects on p38 phosphorylation and inflammatory factor expression.

scholarly journals Constituents of Gastrodia elata and Their Neuroprotective Effects in HT22 Hippocampal Neuronal, R28 Retinal Cells, and BV2 Microglial Cells

Plants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1051
Author(s):  
Hye Mi Kim ◽  
Jaeyoung Kwon ◽  
Kyerim Lee ◽  
Jae Wook Lee ◽  
Dae Sik Jang ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Spectroscopic Data ◽  
Neuronal Cells ◽  
Mass Spectrometry Data ◽  
Microglial Cells ◽  
Nitric Oxide Production ◽  
Gastrodia Elata ◽  
Neuroprotective Effects ◽  
Retinal Cells ◽  
Bv2 Microglial Cells

Gastrodia elata is widely used in traditional medicine and contains various types of metabolites with pharmacological activity. In the course of searching for neuroprotective molecules associated with the potential of G. elata in the treatment of neurodegenerative disorders, two new phenolic compounds (1 and 2) and a new tripeptide (3), together with 16 known compounds (4–19), were isolated from the rhizomes of G. elata. The structures of the compounds were determined by the interpretation of spectroscopic data, including nuclear magnetic resonance and mass spectrometry data. All obtained compounds were assessed for their ability to protect neuronal cells against neurotoxicity and neuroinflammation. Of these, 4 and 5 were found to possess moderate activities in HT22 hippocampal neuronal cells, whereas 2, 6, and 7 showed weak activities in R28 retinal cells. Additionally, compound 9 showed moderate inhibitory activity on lipopolysaccharide-induced nitric oxide production in BV2 microglial cells.

scholarly journals Extracellular CIRP Activates the IL-6Rα/STAT3/Cdk5 Pathway in Neurons

2021 ◽  
Author(s):  
Archna Sharma ◽  
Max Brenner ◽  
Asha Jacob ◽  
Philippe Marambaud ◽  
Ping Wang
Keyword(s):  
Rna Binding ◽  
Neuronal Damage ◽  
Fold Increase ◽  
Time Dependent ◽  
Dependent Manner ◽  
N2a Cells ◽  
Stat3 Phosphorylation ◽  
Bv2 Cells ◽  
Equilibrium Dissociation ◽  
Bv2 Microglial Cells

Abstract Extracellular cold-inducible RNA-binding protein (eCIRP) stimulates microglial inflammation causing neuronal damage during ischemic stroke and is a critical mediator of alcohol-induced cognitive impairment. However, the precise role of eCIRP in mediating neuroinflammation remains unknown. In this study, we report that eCIRP activates neurotoxic cyclin-dependent kinase-5 (Cdk5)/p25 through the induction of IL-6Rα/STAT3 pathway in neurons. Amyloid b (Aβ)-mediated neuronal stress, which is associated with Alzheimer’s disease, increased levels of eCIRP released from BV2 microglial cells. The released eCIRP levels from BV2 cells increased 3.2-fold upon stimulation with conditioned medium from Neuro-2a (N2a) cells containing Aβ compared to control N2a supernatant in a time-dependent manner. Stimulation of N2a cells and primary neurons with eCIRP upregulated the neuronal Cdk5 activator p25 expression in a dose- and time-dependent manner. eCIRP directly induced neuronal STAT3 phosphorylation and p25 increase via its novel receptor IL-6Rα. Next, we showed using surface plasmon resonance that eCIRP-derived peptide C23 inhibited the binding of eCIRP to IL-6Rα at 25 mM, with a 40-fold increase in equilibrium dissociation constant (Kd) value (from 8.08 x 10-8 M to 3.43 x 10-6 M), and completely abrogated the binding at 50 mM. Finally, C23 reversed the eCIRP-induced increase in neuronal STAT3 phosphorylation and p25 levels. In conclusion, the current study demonstrates that upregulation of neuronal IL-6Rα/STAT3/Cdk5 pathway is a key mechanism of eCIRP’s role in neuroinflammation and that C23 as a potent inhibitor of this pathway, has translational potential in neurodegenerative pathologies controlled by eCIRP.

scholarly journals Microglial TonEBP mediates LPS-induced inflammation and memory loss as transcriptional cofactor for NF-κB and AP-1

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Gyu Won Jeong ◽  
Hwan Hee Lee ◽  
Whaseon Lee-Kwon ◽  
Hyug Moo Kwon
Keyword(s):  
Microglial Activation ◽  
Neuronal Damage ◽  
Neuronal Cell Death ◽  
Myeloid Cells ◽  
Memory Loss ◽  
Neuronal Cell ◽  
Microglial Cell Line ◽  
Bv2 Cells ◽  
Pro Inflammatory Cytokines

Abstract Background Microglia are brain-resident myeloid cells involved in the innate immune response and a variety of neurodegenerative diseases. In macrophages, TonEBP is a transcriptional cofactor of NF-κB which stimulates the transcription of pro-inflammatory genes in response to LPS. Here, we examined the role of microglial TonEBP. Methods We used microglial cell line, BV2 cells. TonEBP was knocked down using lentiviral transduction of shRNA. In animals, TonEBP was deleted from myeloid cells using a line of mouse with floxed TonEBP. Cerulenin was used to block the NF-κB cofactor function of TonEBP. Results TonEBP deficiency blocked the LPS-induced expression of pro-inflammatory cytokines and enzymes in association with decreased activity of NF-κB in BV2 cells. We found that there was also a decreased activity of AP-1 and that TonEBP was a transcriptional cofactor of AP-1 as well as NF-κB. Interestingly, we found that myeloid-specific TonEBP deletion blocked the LPS-induced microglia activation and subsequent neuronal cell death and memory loss. Cerulenin disrupted the assembly of the TonEBP/NF-κB/AP-1/p300 complex and suppressed the LPS-induced microglial activation and the neuronal damages in animals. Conclusions TonEBP is a key mediator of microglial activation and neuroinflammation relevant to neuronal damage. Cerulenin is an effective blocker of the TonEBP actions.

scholarly journals PACAP and VIP Modulate LPS-induced Microglial Activation and Trigger Distinct Phenotypic Changes in Murine BV2 Microglial Cells

2021 ◽  
Author(s):  
Jocelyn Karunia ◽  
Aram Niaz ◽  
Mawj Mandwie ◽  
Sarah Thomas Broome ◽  
Kevin A Keay ◽  
...  
Keyword(s):  
Cell Migration ◽  
Microglial Activation ◽  
Activation Markers ◽  
Bv2 Cells ◽  
Bv2 Microglia ◽  
Cell Subpopulations ◽  
Underlying Mechanisms ◽  
And Migration ◽  
Phenotypic Shift ◽  
Bv2 Microglial Cells

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two structurally-related immunosuppressive peptides. However, the underlying mechanisms through which these peptides regulate microglial activity are not fully understood. Using lipopolysaccharide (LPS) to induce an inflammatory challenge, we tested whether PACAP or VIP differentially affected microglial activation, morphology and cell migration. We found that both peptides attenuated LPS-induced expression of the microglial activation markers Iba1 and iNOS (###p<0.001), as well as the pro-inflammatory mediators IL-1β, IL-6, Itgam and CD68 (###p<0.001). In contrast, treatment with PACAP or VIP exerted distinct effects on microglial morphology and migration. PACAP reversed LPS-induced soma enlargement and increased the percentage of small-sized, rounded cells (54.09% vs 12.05% in LPS-treated cells), whereas VIP promoted a phenotypic shift towards cell subpopulations with mid-sized, spindle-shaped soma (48.41% vs 31.36% in LPS-treated). Additionally, PACAP was more efficient than VIP in restoring LPS-induced impairment of cell migration and the expression of urokinase plasminogen activator (uPA) in BV2 cells compared with VIP. These results suggest that whilst both PACAP and VIP exert similar immunosuppressive effects in activated BV2 microglia, each peptide triggers distinctive shifts towards phenotypes of differing morphologies and with differing migration capacities.

scholarly journals Physiologically Relevant Concentrations of Dolutegravir, Emtricitabine, and Efavirenz Induce Distinct Metabolic Alterations in HeLa Epithelial and BV2 Microglial Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Joseph W. George ◽  
Jane E. Mattingly ◽  
Nashanthea J. Roland ◽  
Cassandra M. Small ◽  
Benjamin G. Lamberty ◽  
...  
Keyword(s):  
Side Effects ◽  
Hiv Infection ◽  
Hela Cells ◽  
Microglial Cells ◽  
Redox Activity ◽  
Growth Media ◽  
Bv2 Cells ◽  
Bioenergetic Analysis ◽  
Atp Generation ◽  
Bv2 Microglial Cells

Microglia, the resident brain phagocytes, likely play a key role in human immunodeficiency virus (HIV) infection of the central nervous system (CNS) and subsequent neuropathogenesis; however, the nature of the infection-induced changes that yield damaging CNS effects and the stimuli that provoke microglial activation remains elusive, especially in the current era of using antiretroviral (ARV) drugs for ARV therapy (ART). Altered microglial metabolism can modulate cellular functionality and pathogenicity in neurological disease. While HIV infection itself alters brain energy metabolism, the effect of ARV drugs, particularly those currently used in treatment, on metabolism is understudied. Dolutegravir (DTG) and emtricitabine (FTC) combination, together with tenofovir (TAF or TDF), is one of the recommended first line treatments for HIV. Despite the relatively good tolerability and safety profile of FTC, a nucleoside reverse transcriptase inhibitor, and DTG, an integrase inhibitor, adverse side effects have been reported and highlight a need to understand off-target effects of these medications. We hypothesized that similar to previous ART regimen drugs, DTG and FTC side effects involve mitochondrial dysfunction. To increase detection of ARV-induced mitochondrial effects, highly glycolytic HeLa epithelial cells were forced to rely on oxidative phosphorylation by substituting galactose for glucose in the growth media. We assessed ATP levels, resazurin oxidation-reduction (REDOX), and mitochondrial membrane potential following 24-hour exposure (to approximate effects of one dose equivalent) to DTG, FTC, and efavirenz (EFV, a known mitotoxic ARV drug). Further, since microglia support productive HIV infection, act as latent HIV cellular reservoirs, and when dysfunctional likely contribute to HIV-associated neurocognitive disorders, the experiments were repeated using BV2 microglial cells. In HeLa cells, FTC decreased mitochondrial REDOX activity, while DTG, similar to EFV, impaired both mitochondrial ATP generation and REDOX activity. In contrast to HeLa cells, DTG increased cellular ATP generation and mitochondrial REDOX activity in BV2 cells. Bioenergetic analysis revealed that DTG, FTC, and EFV elevated BV2 cell mitochondrial respiration. DTG and FTC exposure induced distinct mitochondrial functional changes in HeLa and BV2 cells. These findings suggest cell type-specific metabolic changes may contribute to the toxic side effects of these ARV drugs.

scholarly journals Inhibition of PDE1-B by Vinpocetine Regulates Microglial Exosomes and Polarization Through Enhancing Autophagic Flux for Neuroprotection Against Ischemic Stroke

2021 ◽  
Vol 8 ◽  
Author(s):  
Jiankun Zang ◽  
Yousheng Wu ◽  
Xuanlin Su ◽  
Tianyuan Zhang ◽  
Xionglin Tang ◽  
...  
Keyword(s):  
Crucial Role ◽  
Neuronal Damage ◽  
Neuronal Survival ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Autophagic Flux ◽  
Exosome Biogenesis ◽  
Bv2 Cells ◽  
M1 Phenotype

Exosomes contribute to cell–cell communications. Emerging evidence has shown that microglial exosomes may play crucial role in regulation of neuronal functions under ischemic conditions. However, the underlying mechanisms of microglia-derived exosome biosynthesis are largely unknown. Herein, we reported that the microglial PDE1-B expression was progressively elevated in the peri-infarct region after focal middle cerebral artery occlusion. By an oxygen-glucose-deprivation (OGD) ischemic model in cells, we found that inhibition of PDE1-B by vinpocetine in the microglial cells promoted M2 and inhibited M1 phenotype. In addition, knockdown or inhibition of PDE1-B significantly enhanced the autophagic flux in BV2 cells, and vinpocetine-mediated suppression of M1 phenotype was dependent on autophagy in ischemic conditions. Co-culture of BV2 cells and neurons revealed that vinpocetine-treated BV2 cells alleviated OGD-induced neuronal damage, and treatment of BV2 cells with 3-MA abolished the observed effects of vinpocetine. We further demonstrated that ischemia and vinpocetine treatment significantly altered microglial exosome biogenesis and release, which could be taken up by recipient neurons and regulated neuronal damage. Finally, we showed that the isolated exosome per se from conditioned BV2 cells is sufficient to regulate cortical neuronal survival in vivo. Taken together, these results revealed a novel microglia-neuron interaction mediated by microglia-derived exosomes under ischemic conditions. Our findings further suggest that PDE1-B regulates autophagic flux and exosome biogenesis in microglia which plays a crucial role in neuronal survival under cerebral ischemic conditions.

scholarly journals Inhibitory Effect of Gualou Guizhi Decoction on Microglial Inflammation and Neuron Injury by Promoting Anti-Inflammation via Targeting mmu-miR-155

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Haixia Hu ◽  
Xinghua Zhong ◽  
Xinjun Lin ◽  
Jinbo Yang ◽  
Xiaoqin Zhu
Keyword(s):  
Ischemic Stroke ◽  
Cell Line ◽  
Conditioned Medium ◽  
Neuronal Damage ◽  
Apoptotic Cell ◽  
Neuroprotective Effects ◽  
Ht22 Cells ◽  
Guizhi Decoction ◽  
Bv2 Cells ◽  
Microglial Inflammation

Gualou Guizhi decoction (GLGZD) treatment exerts neuroprotective effects and promotes spasticity following ischemic stroke. However, the molecular mechanism of GLGZD treatment on ischemic stroke remains unclear. Our previous study indicated that GLGZD ameliorates neuronal damage caused by secondary inflammatory injury induced by microglia. In the present study, we investigate the potential mechanism of GLGZD treatment on neuron damage induced by neuroinflammation via mmu-miR-155 in vitro. The HT22 cell line and the BV2 cell line were exposed to oxygen/glucose-deprive (OGD) conditions; the conditioned medium was prepared using the supernatants from OGD-stimulated BV2 cells after pretreating with GLGZD. Cell viability was determined by MTT assays; levels of released inflammatory cytokines were assessed using the BioPlex system. mmu-miR-155 and its targeting genes were detected using real-time reverse transcription polymerase chain reaction (RT-PCR). The expression of anti-inflammatory proteins was evaluated by Western blotting. DAPI staining was used to test the apoptotic cells. Our results showed that GLGZD pretreatment significantly induced IL10 release and decreased the production of TNF-α, IL6, and IFN-γ. In addition, GLGZD markedly attenuated mmu-miR-155 expression and its downstream SOCS1, SMAD2, SHIP1, and TAB2 expression levels. The DAPI-stained apoptotic cell death and caspase-3 activation in HT22 cells exposed to the conditioned medium were reversed by GLGZD treatment. Our findings suggested that GLGZD pretreatment downregulates the mmu-miR-155 signaling, which inhibits microglial inflammation, thereby resulting in the suppression of neuron apoptosis after OGD stress. The underlying mechanisms may provide the support for GLGZD treatment of cerebral ischemic injury.

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